Jiayu Wang

By Nicole L. Michmerhuizen, Jiayu Wang and J. Chad Brenner

The identification of drug resistance pathways and approaches to target these pathways remains a significant and important challenge in cancer biology. Here, we address this challenge in the context of ongoing efforts to advance phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of PI3K-aberrant cancers. While PI3K inhibitors have had tremendous success in some diseases, such as breast cancer, early clinical trials in other malignancies, such as head and neck squamous cell carcinoma (HNSCC), have not had the same level of success. Since HNSCC and other cancers display relatively high PI3K pathway alteration rates (>45%), these underwhelming results suggest that additional or unexpected factors may contribute to the lower response rates. Here, we highlight some of the emerging functional genomic and sequencing approaches being used to identify predictive biomarkers of PI3K inhibitor response using both cancer cell lines and clinical trial specimens. Importantly, these approaches have uncovered both innate genetic and adaptive mechanisms driving PI3K inhibitor resistance. In this chapter, we describe recent technological advances that have revolutionized our understanding of PI3K inhibitor resistance pathways in HNSCC and highlight how these and other approaches lay the groundwork to make significant strides in our understanding of molecular pharmacology in the cancer field.

Part of the book: Molecular Pharmacology